Synthesizing drug-organic-acid-anhydride conjugates without using coupling reagent

A method for synthesizing a drug-organic-acid-anhydride conjugate using docetaxel as a drug, the method comprising:

• mixing aconitic anhydride with a chlorinating reagent to produce a first liquid mixture by adding drop-wise the chlorinating reagent to the aconitic anhydride, wherein the chlorinating reagent comprises an reagent selected from the group consisting of phosphorus pentachloride (PCl3), thionyl chloride, and oxalyl chloride;
• dissolving the first liquid mixture in an organic solvent to produce a dissolved mixture, wherein the organic solvent comprises a solvent selected from the group consisting of methylene chloride, chloroform, and tetrahydrofuran (THF);
• stirring the dissolved mixture;
• evaporating the organic solvent from the dissolved mixture to produce a second mixture;
• washing the second mixture with an impurity remover to remove impurities and to produce aconitic anhydride chloride, wherein the impurity remover is cyclohexane, wherein washing the second mixture with the impurity remover comprises dispersing the second mixture in the cyclohexane and centrifuging and decanting the cyclohexane to remove the impurities to produce the aconitic anhydride chloride;
• and
• mixing the docetaxel with the aconitic anhydride chloride to produce the drug-organic- acid-anhydride conjugate, wherein the drug-organic-acid-anhydride conjugate is a docetaxel- aconitic anhydride conjugate of Formula DTX-AA3:
• Formula DTX-AA3.